Dopaminergic axon tracts within a hyaluronic acid hydrogel encasement for implantation to restore the nigrostriatal pathway

Gordián-Vélez, Wisberty J.; Kd, Browne; Jh, Galarraga; Duda, Jeffrey T.; Ra, España; Hi, Chen; Ja, Burdick; Cullen, D. Kacy

doi:10.1101/2021.07.03.451006

Cited by 4 publications

(7 citation statements)

References 68 publications

(101 reference statements)

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“…Therefore, the axonal contraction rates achieved in this system would likely be influenced by the ECM constituents, and it would be worthwhile to characterize these effects in future studies. Similarly, changing the composition of the hydrogel micro-column would also influence the axonal contraction rate as the stiffness provided by the outer shell varies depending on the biomaterial ( Gordián-Vélez et al, 2021b ). We have previously seen an effect on the growth rate of primary rat dopaminergic neurons by changing the micro-column from agarose to hyaluronic acid ( Gordián-Vélez et al, 2021b ).…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, changing the composition of the hydrogel micro-column would also influence the axonal contraction rate as the stiffness provided by the outer shell varies depending on the biomaterial ( Gordián-Vélez et al, 2021b ). We have previously seen an effect on the growth rate of primary rat dopaminergic neurons by changing the micro-column from agarose to hyaluronic acid ( Gordián-Vélez et al, 2021b ). Cell-material interactions could further play a role in tissue mechanics if the hydrogel micro-column provide adhesion sites to the soma when the neural network is formed.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously seen an effect on the growth rate of primary rat dopaminergic neurons by changing the micro-column from agarose to hyaluronic acid (Gordián-Vélez et al, 2021b). Cell-material interactions could further play a role in tissue mechanics if the hydrogel micro-column provide adhesion sites to the soma when the neural network is formed.…”

Section: Discussionmentioning

confidence: 99%

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Generation of contractile forces by three-dimensional bundled axonal tracts in micro-tissue engineered neural networks

Chouhan,

Gordián Vélez,

Struzyna

et al. 2024

Front. Mol. Neurosci.

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Axonal extension and retraction are ongoing processes that occur throughout all developmental stages of an organism. The ability of axons to produce mechanical forces internally and respond to externally generated forces is crucial for nervous system development, maintenance, and plasticity. Such axonal mechanobiological phenomena have typically been evaluated in vitro at a single-cell level, but these mechanisms have not been studied when axons are present in a bundled three-dimensional (3D) form like in native tissue. In an attempt to emulate native cortico-cortical interactions under in vitro conditions, we present our approach to utilize previously described micro-tissue engineered neural networks (micro-TENNs). Here, micro-TENNs were comprised of discrete populations of rat cortical neurons that were spanned by 3D bundled axonal tracts and physically integrated with each other. We found that these bundled axonal tracts inherently exhibited an ability to generate contractile forces as the microtissue matured. We therefore utilized this micro-TENN testbed to characterize the intrinsic contractile forces generated by the integrated axonal tracts in the absence of any external force. We found that contractile forces generated by bundled axons were dependent on microtubule stability. Moreover, these intra-axonal contractile forces could simultaneously generate tensile forces to induce so-called axonal “stretch-growth” in different axonal tracts within the same microtissue. The culmination of axonal contraction generally occurred with the fusion of both the neuronal somatic regions along the axonal tracts, therefore perhaps showing the innate tendency of cortical neurons to minimize their wiring distance, a phenomenon also perceived during brain morphogenesis. In future applications, this testbed may be used to investigate mechanisms of neuroanatomical development and those underlying certain neurodevelopmental disorders.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Generation of contractile forces by three-dimensional bundled axonal tracts in micro-tissue engineered neural networks

Chouhan,

Gordián Vélez,

Struzyna

et al. 2024

Front. Mol. Neurosci.

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“…In a rat parkinsonian model, TE-NSP neurons survived in the SNpc, and axons extended to integrate within the striatum [95]. Also, TE-NSPs fabricated using hPSC-derived DA neurons were grown to scaled-up dimensions, comprising 200,000 DA neurons with axonal projections of >2 cm [93]. Seeding of columns with hPSC-derived DA cells and subsequent injection may therefore more directly address the design needs of neural replacement therapy for PD.…”

Section: Tissue-engineered Constructs To Reconstruct the Nigrostriata...mentioning

confidence: 99%

“…This lack of feedback regulation may limit the effectiveness of DA cell therapy and contribute to increased risk of side effects such as dyskinesias. TE-NSPs, comprising a miniature tubular hydrogel seeded with dopaminergic neurons and extracellular matrix components [89][90][91][92][93], may allow for more effective restoration of the motor control feedback circuit between the SN and striatum (Figure 2). While TE-NSPs constructs typically have a diameter of only a few hundred microns, they can support long axonal growth.…”

Section: Tissue-engineered Constructs To Reconstruct the Nigrostriata...mentioning

confidence: 99%

Cell Replacement Therapy for Brain Repair: Recent Progress and Remaining Challenges for Treating Parkinson’s Disease and Cortical Injury

Harary,

Jgamadze,

Kim

et al. 2023

Brain Sciences

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Neural transplantation represents a promising approach to repairing damaged brain circuitry. Cellular grafts have been shown to promote functional recovery through “bystander effects” and other indirect mechanisms. However, extensive brain lesions may require direct neuronal replacement to achieve meaningful restoration of function. While fetal cortical grafts have been shown to integrate with the host brain and appear to develop appropriate functional attributes, the significant ethical concerns and limited availability of this tissue severely hamper clinical translation. Induced pluripotent stem cell-derived cells and tissues represent a more readily scalable alternative. Significant progress has recently been made in developing protocols for generating a wide range of neural cell types in vitro. Here, we discuss recent progress in neural transplantation approaches for two conditions with distinct design needs: Parkinson’s disease and cortical injury. We discuss the current status and future application of injections of dopaminergic cells for the treatment of Parkinson’s disease as well as the use of structured grafts such as brain organoids for cortical repair.

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Emergent structural and functional properties of hippocampal multi-cellular aggregates

Acero,

Das,

Rivellini

et al. 2023

Front. Neurosci.

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Hippocampal neural networks are distinctly capable of integrating multi-modal sensory inputs to drive memory formation. Neuroscientific investigations using simplified in vitro models have greatly relied on planar (2D) neuronal cultures made from dissociated tissue. While these models have served as simple, cost-effective, and high-throughput tools for examining various morphological and electrophysiological characteristics of hippocampal networks, 2D cultures fail to reconstitute critical elements of the brain microenvironment that may be necessary for the emergence of sophisticated integrative network properties. To address this, we utilized a forced aggregation technique to generate high-density (>100,000 cells/mm3) multi-cellular three-dimensional aggregates using rodent embryonic hippocampal tissue. We contrasted the emergent structural and functional properties of aggregated (3D) and dissociated (2D) cultures over 28 days in vitro (DIV). Hippocampal aggregates displayed robust axonal fasciculation across large distances and significant neuronal polarization, i.e., spatial segregation of dendrites and axons, at earlier time points compared to dissociated cultures. Moreover, we found that astrocytes in aggregate cultures self-organized into non-overlapping quasi-domains and developed highly stellate morphologies resembling astrocyte structures in vivo. We maintained cultures on multi-electrode arrays (MEAs) to assess spontaneous electrophysiological activity for up to 28 DIV. We found that 3D networks of aggregated cultures developed highly synchronized networks and with high burstiness by 28 DIV. We also demonstrated that dual-aggregate networks became active by 7 DIV, in contrast to single-aggregate networks which became active and developed synchronous bursting activity with repeating motifs by 14 DIV. Taken together, our findings demonstrate that the high-density, multi-cellular, 3D microenvironment of hippocampal aggregates supports the recapitulation of emergent biofidelic morphological and functional properties. Our findings suggest that neural aggregates may be used as segregated, modular building blocks for the development of complex, multi-nodal neural network topologies.

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Dopaminergic axon tracts within a hyaluronic acid hydrogel encasement for implantation to restore the nigrostriatal pathway

Cited by 4 publications

References 68 publications

Generation of contractile forces by three-dimensional bundled axonal tracts in micro-tissue engineered neural networks

Generation of contractile forces by three-dimensional bundled axonal tracts in micro-tissue engineered neural networks

Cell Replacement Therapy for Brain Repair: Recent Progress and Remaining Challenges for Treating Parkinson’s Disease and Cortical Injury

Emergent structural and functional properties of hippocampal multi-cellular aggregates

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